9-128689655-G-GAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAATGAAATA

Variant names:

• chr9-128689655-G-GAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAATGAAATA
• rs745491546
• NM_003011.4:c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAATGAAATA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_003011.4(SET):​c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAATGAAATA variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000377 in 1,060,136 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: SET NM_003011.4 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03

Genes affected

SET (HGNC:10760): (SET nuclear proto-oncogene) The protein encoded by this gene inhibits acetylation of nucleosomes, especially histone H4, by histone acetylases (HAT). This inhibition is most likely accomplished by masking histone lysines from being acetylated, and the consequence is to silence HAT-dependent transcription. The encoded protein is part of a complex localized to the endoplasmic reticulum but is found in the nucleus and inhibits apoptosis following attack by cytotoxic T lymphocytes. This protein can also enhance DNA replication of the adenovirus genome. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SET	NM_003011.4	c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAATGAAATA		splice_donor_variant, intron_variant	Intron 1 of 7	ENST00000322030.13	NP_003002.2
SET	NM_001122821.2	c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAATGAAATA		intron_variant	Intron 1 of 7		NP_001116293.1
SET	NM_001374326.1	c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAATGAAATA		intron_variant	Intron 2 of 8		NP_001361255.1
SET	NM_001248000.2	c.47-1515_47-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAATGAAATA		intron_variant	Intron 1 of 7		NP_001234929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SET	ENST00000322030.13	c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAATGAAATA		splice_donor_variant, intron_variant	Intron 1 of 7	1	NM_003011.4	ENSP00000318012.9

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.0000807 AC: 8 AN: 99180 Hom.: 0 AF XY: 0.0000688 AC XY: 4 AN XY: 58128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000162

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000115

Gnomad FIN exome AF: 0.0000860

Gnomad NFE exome AF: 0.0000737

Gnomad OTH exome AF: 0.000423

GnomAD4 exome AF: 0.00000377 AC: 4 AN: 1060136 Hom.: 0 Cov.: 15 AF XY: 0.00000388 AC XY: 2 AN XY: 516012

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000491

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000231

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs745491546; hg19: chr9-131451934;